tbuckley/cabot-search huggingface dataset:
Reconciling Mouse and Human Immunology at the Altar of Genetics
Authors: Philippe Gros, Jean-Laurent Casanova
Journal: Annual Review of Immunology (2022)

Immunity to infection has been extensively studied in humans and mice bearing naturally occurring or experimentally introduced germline mutations. Mouse studies are sometimes neglected by human immunologists, on the basis that mice are not humans and the infections studied are experimental and not natural. Conversely, human studies are sometimes neglected by mouse immunologists, on the basis of the uncontrolled conditions of study and small numbers of patients. However, both sides would agree that the infectious phenotypes of patients with inborn errors of immunity often differ from those of the corresponding mutant mice. Why is that? We argue that this important question is best addressed by revisiting and reinterpreting the findings of both mouse and human studies from a genetic perspective. Greater caution is required for reverse-genetics studies than for forward-genetics studies, but genetic analysis is sufficiently strong to define the studies likely to stand the test of time. Genetically robust mouse and human studies can provide invaluable complementary insights into the mechanisms of immunity to infection common and specific to these two species.
Enteropathogenic <i>Escherichia coli</i> regulates host-cell mitochondrial morphology
Authors: Jennifer Lising Roxas, Shylaja Ramamurthy, Katie Cocchi, Ilga Rutins, Anusha Harishankar, Al Agellon, John Scott Wilbur, Gresa Sylejmani, Gayatri Vedantam, V.K. Viswanathan
Journal: Gut Microbes (2022)

The diarrheagenic pathogen enteropathogenic Escherichia coli is responsible for significant childhood mortality and morbidity. EPEC and related attaching-and-effacing (A/E) pathogens use a type III secretion system to hierarchically deliver effector proteins into host cells and manipulate epithelial structure and function. Subversion of host mitochondrial biology is a key aspect of A/E pathogen virulence strategy, but the mechanisms remain poorly defined. We demonstrate that the early-secreted effector EspZ and the late-secreted effector EspH have contrasting effects on host mitochondrial structure and function. EspZ interacts with FIS1, a protein that induces mitochondrial fragmentation and mitophagy. Infection of epithelial cells with either wildtype EPEC or an isogenic espZ deletion mutant (ΔespZ) robustly upregulated FIS1 abundance, but a marked increase in mitochondrial fragmentation and mitophagy was seen only in ΔespZ-infected cells. FIS1-depleted cells were protected against ΔespZ-induced fission, and EspZ-expressing transfected epithelial cells were protected against pharmacologically induced mitochondrial fission and membrane potential disruption. Thus, EspZ interacts with FIS1 and blocks mitochondrial fragmentation and mitophagy. In contrast to WT EPEC, ΔespH-infected epithelial cells had minimal FIS1 upregulation and exhibited hyperfused mitochondria. Consistent with the contrasting impacts on organelle shape, mitochondrial membrane potential was preserved in ΔespH-infected cells, but profoundly disrupted in ΔespZ-infected cells. Collectively, our studies reveal hitherto unappreciated roles for two essential EPEC virulence factors in the temporal and dynamic regulation of host mitochondrial biology.
Value of bone marrow examination in determining response to therapy in patients with multiple myeloma in the context of mass spectrometry-based M-protein assessment
Authors: Jean-Sébastien Claveau, David L. Murray, Angela Dispenzieri, Prashant Kapoor, Moritz Binder, Francis Buadi, David Dingli, Amie Fonder, Morie Gertz, Wilson Gonsalves, Suzanne Hayman, Miriam Hobbs, Yi Lisa Hwa, Taxiarchis Kourelis, Martha Lacy, Nelson Leung, Yi Lin, Rahma Warsame, Robert A. Kyle, Vincent Rajkumar, Shaji K. Kumar
Journal: Leukemia (2022)
Racial/Ethnic Differences in Associations Between Traumatic Childhood Experiences and Both Metabolic Syndrome Prevalence and Type 2 Diabetes Risk Among a Cohort of U.S. Women
Authors: Symielle A. Gaston, Nyree M. Riley, Christine G. Parks, Jennifer M.P. Woo, Dale P. Sandler, Chandra L. Jackson
Journal: Diabetes Care (2022)

OBJECTIVE Childhood adversity has been associated with metabolic syndrome (MetS) and type 2 diabetes risk in adulthood. However, studies have yet to investigate traumatic childhood experiences (TCEs) beyond abuse and neglect (e.g., natural disaster) while considering potential racial/ethnic differences. RESEARCH DESIGN AND METHODS To investigate race/ethnicity as a potential modifier of the association between TCEs, MetS, and type 2 diabetes, we used prospectively collected data from 42,173 eligible non-Hispanic White (NHW; 88%), Black/African American (BAA; 7%), and Hispanic/Latina (4%) Sister Study participants (aged 35–74 years) enrolled from 2003 to 2009. A modified Brief Betrayal Trauma Survey captured TCEs. At least three prevalent metabolic abnormalities defined MetS, and self-report of a new diagnosis during the study period defined type 2 diabetes. We used adjusted Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs for type 2 diabetes over a mean ± SD follow-up of 11.1 ± 2.7 years, overall and by race/ethnicity. We also tested for modification and mediation by MetS. RESULTS Incident cases of type 2 diabetes were reported (n = 2,479 among NHW, 461 among BAA, and 281 among Latina participants). Reporting any TCEs (50% among NHW, 53% among BAA, and 51% among Latina participants) was associated with a 13% higher risk of type 2 diabetes (HR 1.13; 95% CI 1.04–1.22). Associations were strongest among Latina participants (HR 1.64 [95% CI 1.21–2.22] vs. 1.09 for BAA and NHW). MetS was not a modifier but mediated (indirect effect, HR 1.01 [95% CI 1.00–1.01]; P = 0.02) the overall association. CONCLUSIONS TCE and type 2 diabetes associations varied by race/ethnicity and were partially explained by MetS.
Germline variants associated with toxicity to immune checkpoint blockade
Authors: Stefan Groha, Sarah Abou Alaiwi, Wenxin Xu, Vivek Naranbhai, Amin H. Nassar, Ziad Bakouny, Talal El Zarif, Renee Maria Saliby, Guihong Wan, Ahmad Rajeh, Elio Adib, Pier V. Nuzzo, Andrew L. Schmidt, Chris Labaki, Biagio Ricciuti, Joao Victor Alessi, David A. Braun, Sachet A. Shukla, Tanya E. Keenan, Eliezer Van Allen, Mark M. Awad, Michael Manos, Osama Rahma, Leyre Zubiri, Alexandra-Chloe Villani, Benjamin Fairfax, Christian Hammer, Zia Khan, Kerry Reynolds, Yevgeniy Semenov, Deborah Schrag, Kenneth L. Kehl, Matthew L. Freedman, Toni K. Choueiri, Alexander Gusev
Journal: Nature Medicine (2022)
OUTCOMES OF PATIENTS WITH ACUTE CORONARY SYNDROMES UNDERGOING CHRONIC TOTAL OCCLUSION PERCUTANEOUS CORONARY INTERVENTION
Authors: Bahadir Simsek, Spyridon Kostantinis, Judit Karacsonyi, Khaldoon Alaswad, Farouc A. Jaffer, Darshan Doshi, Jaikirshan J. Khatri, Paul Poommipanit, Sevket Gorgulu, Nazif Aygul, Nidal Abi Rafeh, Oleg Krestianinov, James W. Choi, Barry F. Uretsky, Rhian E. Davies, Omer Goktekin, Ahmed Mohamed ElGuindy, Brian K. Jefferson, Mitul P. Patel, Bavana V. Rangan, Athanasios Rempakos, Salman S. Allana, Yader Sandoval, M. Nicholas Burke, Emmanouil S. Brilakis
Journal: Journal of the American College of Cardiology (2023)
Concomitant Use of Sulfonylureas and β-Blockers and the Risk of Severe Hypoglycemia Among Patients With Type 2 Diabetes: A Population-Based Cohort Study
Authors: Jenny Dimakos, Ying Cui, Robert W. Platt, Christel Renoux, Kristian B. Filion, Antonios Douros
Journal: Diabetes Care (2022)

OBJECTIVE The hypoglycemic potential of β-blockers among users of sulfonylureas, drugs that strongly increase the risk of this potentially fatal adverse effect, is not well understood. Our population-based cohort study assessed the potential association between concomitant use of sulfonylureas and β-blockers versus use of sulfonylureas alone and the risk of severe hypoglycemia. RESEARCH DESIGN AND METHODS Using the U.K. Clinical Practice Research Datalink Aurum, we included patients initiating sulfonylureas between 1998 and 2020, excluding those with β-blocker use in the past 6 months. Time-dependent Cox models estimated hazard ratios (HRs) with 95% CIs of severe hypoglycemia (hospitalization with or death resulting from hypoglycemia; ICD-10 codes E16.0, E16.1, and E16.2) associated with current concomitant use of sulfonylureas and β-blockers compared with current sulfonylurea use alone, adjusted for baseline confounders. We also compared current concomitant use of sulfonylureas and non-cardioselective versus cardioselective β-blockers. RESULTS Our cohort included 252,869 initiators of sulfonylureas (mean age 61.3 years; 43% female). Median follow-up was 7.9 years. The crude incidence rate of severe hypoglycemia was 7.8 per 1,000 per year. Concomitant use of sulfonylureas and β-blockers was associated with an increased risk of severe hypoglycemia compared with sulfonylurea use alone (HR 1.53; 95% CI 1.42–1.65). There was no difference in the risk between concomitant use of sulfonylureas and noncardioselective β-blockers and concomitant use of sulfonylureas and cardioselective β-blockers (HR 0.95; 95% CI 0.74–1.24). CONCLUSIONS β-blockers could further increase the risk of severe hypoglycemia when used concurrently with sulfonylureas. β-blocker cardioselectivity did not seem to play a major role in this regard.
Effectiveness of BNT162b2 and CoronaVac COVID-19 vaccination against asymptomatic and symptomatic infection of SARS-CoV-2 omicron BA.2 in Hong Kong: a prospective cohort study
Authors: Nicole Ngai Yung Tsang, Hau Chi So, Benjamin J Cowling, Gabriel M Leung, Dennis Kai Ming Ip
Journal: The Lancet Infectious Diseases (2022)
Randomized Trials Fit for the 21st Century: A Joint Opinion From the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation
Authors: Louise Bowman, Franz Weidinger, Michelle A. Albert, Edward T.A. Fry, Fausto J. Pinto, Stephan Achenbach, Louise Bowman, Barbara Casadei, Rory Collins, Philip J. Devereaux, Pamela S. Douglas, Ole Frobert, Shinya Goto, Cindy Grines, Robert A. Harrington, Richard Haynes, Judith S. Hochman, Stefan James, Paulus Kirchhof, Michel Komajda, Carolyn S.P. Lam, Martin Landray, Aldo Maggioni, John McMurray, Nick Medhurst, Bruce Neal, Lars Rydén, Holger Thiele, Isabelle Van Gelder, Lars Wallentin, Salim Yusuf, Faiez Zannad
Journal: Circulation (2022)
IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma
Authors: Chelsea A. Taylor, Robert A. Watson, Orion Tong, Weiyu Ye, Isar Nassiri, James J. Gilchrist, Alba Verge de los Aires, Piyush Kumar Sharma, Surya Koturan, Rosalin A. Cooper, Victoria K. Woodcock, Elsita Jungkurth, Brian Shine, Nicholas Coupe, Miranda J. Payne, David N. Church, Vivek Naranbhai, Stefan Groha, Paul Emery, Kulveer Mankia, Matthew L. Freedman, Toni K. Choueiri, Mark R. Middleton, Alexander Gusev, Benjamin P. Fairfax
Journal: Nature Medicine (2022)

Abstract Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7 . We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8 + T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma.
Asxl1 deletion disrupts MYC and RNA polymerase II function in granulocyte progenitors
Authors: Theodore P. Braun, Joseph Estabrook, Zachary Schonrock, Brittany M. Curtiss, Lucie Darmusey, Jommel Macaraeg, Trevor Enright, Cody Coblentz, Rowan Callahan, William Yashar, Akram Taherinasab, Hisham Mohammed, Daniel J. Coleman, Brian J. Druker, Emek Demir, Theresa A. Lusardi, Julia E. Maxson
Journal: Leukemia (2022)
Altered and allele-specific open chromatin landscape reveals epigenetic and genetic regulators of innate immunity in COVID-19
Authors: Bowen Zhang, Zhenhua Zhang, Valerie A.C.M. Koeken, Saumya Kumar, Michelle Aillaud, Hsin-Chieh Tsay, Zhaoli Liu, Anke R.M. Kraft, Chai Fen Soon, Ivan Odak, Berislav Bošnjak, Anna Vlot, Morris A. Swertz, Uwe Ohler, Robert Geffers, Thomas Illig, Jochen Huehn, Antoine-Emmanuel Saliba, Leif Erik Sander, Reinhold Förster, Cheng-Jian Xu, Markus Cornberg, Leon N. Schulte, Yang Li
Journal: Cell Genomics (2022)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes severe COVID-19 in some patients and mild COVID-19 in others. Dysfunctional innate immune responses have been identified to contribute to COVID-19 severity, but the key regulators are still unknown. Here, we present an integrative single-cell multi-omics analysis of peripheral blood mononuclear cells from hospitalized and convalescent COVID-19 patients. In classical monocytes, we identified genes that were potentially regulated by differential chromatin accessibility. Then, sub-clustering and motif-enrichment analyses revealed disease condition-specific regulation by transcription factors and their targets, including an interaction between C/EBPs and a long-noncoding RNA LUCAT1, which we validated through loss-of-function experiments. Finally, we investigated genetic risk variants that exhibit allele-specific open chromatin (ASoC) in COVID-19 patients and identified a SNP rs6800484-C, which is associated with lower expression of CCR2 and may contribute to higher viral loads and higher risk of COVID-19 hospitalization. Altogether, our study highlights the diverse genetic and epigenetic regulators that contribute to COVID-19.
A Novel Approach to Temperature Profiling in Relation to Clinical Outcomes in Oncological Patients with Neutropenia
Authors: Catia Cilloniz, Antoni Torres
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"A Novel Approach to Temperature Profiling in Relation to Clinical Outcomes and Oncological Patients with Neutropenia." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –
Correction to: Organ dysfunction, thrombotic events, and malignancies in patients with idiopathic multicentric Castleman disease: a population-level US health claims analysis
Authors: Sudipto Mukherjee, Karan Kanhai, David Kauffman, Rabecka Martin, Jeremy S. Paige, Anirvan Ghosh, Hannah Kannan, Francis Shupo, David C. Fajgenbaum
Journal: Leukemia (2022)
Reporting the early stage clinical evaluation of virtual-reality-based intervention trials: RATE-VR
Authors: Johan H. Vlake, Jasper van Bommel, Giuseppe Riva, Brenda K. Wiederhold, Pietro Cipresso, Albert Skip Rizzo, Cristina Botella, Lotty Hooft, O. Joseph Bienvenu, Bart Geerts, Evert-Jan Wils, Diederik Gommers, Michel E. van Genderen
Journal: Nature Medicine (2022)
Dual inhibition of CHK1/FLT3 enhances cytotoxicity and overcomes adaptive and acquired resistance in FLT3-ITD acute myeloid leukemia
Authors: Kailong Jiang, Xuemei Li, Chang Wang, Xiaobei Hu, Peipei Wang, Lexian Tong, Yutong Tu, Beijing Chen, Tingting Jin, Tao Wang, Hanlin Wang, Yubing Han, Renzhao Gui, Jianmin Yang, Tao Liu, Jia Li, Yubo Zhou
Journal: Leukemia (2022)
Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency
Authors: Romain Lévy, Florian Gothe, Mana Momenilandi, Thomas Magg, Marie Materna, Philipp Peters, Johannes Raedler, Quentin Philippot, Anita Lena Rack-Hoch, David Langlais, Mathieu Bourgey, Anna-Lisa Lanz, Masato Ogishi, Jérémie Rosain, Emmanuel Martin, Sylvain Latour, Natasha Vladikine, Marco Distefano, Taushif Khan, Franck Rapaport, Marian S. Schulz, Ursula Holzer, Anders Fasth, Georgios Sogkas, Carsten Speckmann, Arianna Troilo, Venetia Bigley, Anna Roppelt, Yael Dinur-Schejter, Ori Toker, Karen Helene Bronken Martinsen, Roya Sherkat, Ido Somekh, Raz Somech, Dror S. Shouval, Jörn-Sven Kühl, Winnie Ip, Elizabeth M. McDermott, Lucy Cliffe, Ahmet Ozen, Safa Baris, Hemalatha G. Rangarajan, Emmanuelle Jouanguy, Anne Puel, Jacinta Bustamante, Marie-Alexandra Alyanakian, Mathieu Fusaro, Yi Wang, Xiao-Fei Kong, Aurélie Cobat, David Boutboul, Martin Castelle, Claire Aguilar, Olivier Hermine, Morgane Cheminant, Felipe Suarez, Alisan Yildiran, Aziz Bousfiha, Hamoud Al-Mousa, Fahad Alsohime, Deniz Cagdas, Roshini S. Abraham, Alan P. Knutsen, Borre Fevang, Sagar Bhattad, Ayca Kiykim, Baran Erman, Tugba Arikoglu, Ekrem Unal, Ashish Kumar, Christoph B. Geier, Ulrich Baumann, Bénédicte Neven, Julie Calas, Elizabeth Feuille, Angela Chan, Gozde Yesil, Justine Nammour, Élise Bandet, Capucine Picard, Ibtihal Benhsaien, Peter Lang, Faranaz Atschekzei, Klaus Warnatz, Sophie Hambleton, Mukesh Desai, Elif Karakoc-Aydiner, Burcu Kolukisa, Saleh Al-Muhsen, Mohammed F. Alosaimi, Funda Cipe, Anas M. Alazami, Gonca Hancioglu, Bilge Can Meydan, Hanne S. Sorte, Asbjørg Stray-Pedersen, Geetha Mammayil, Nazan Tökmeci, Anna Shcherbina, Polina Stepensky, Adeeb NaserEddin, Claire Rouzaud, Akihiro Hoshino, Oded Shamriz, Oren Ledder, Maria Elena Maccari, Carla N. Castro, Bodo Grimbacher, Reinhold E. Schmidt, Matthew Collin, Victorya Zakharova, Meino Rohlfs, Christoph Walz, Laurent Abel, Bernard Malissen, Nico Marr, Christoph Klein, Jean-Laurent Casanova, Fabian Hauck, Vivien Béziat
Journal: The Journal of Experimental Medicine (2022)

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.
Targeting inorganic nanoparticles to tumors using biological membrane‐coated technology
Authors: Yuanyuan Zhang, Qian Chen, Yefei Zhu, Manman Pei, Kairuo Wang, Xiao Qu, Yang Zhang, Jie Gao, Huanlong Qin
Journal: MedComm (2022)

Abstract Inorganic nanoparticles have extensively revolutionized the effectiveness of cancer therapeutics due to their distinct physicochemical properties. However, the therapeutic efficiency of inorganic nanoparticles is greatly hampered by the complex tumor microenvironment, patient heterogeneity, and systemic nonspecific toxicity. The biomimetic technology based on biological membranes (cell‐ or bacteria‐derived membranes) is a promising strategy to confer unique characteristics to inorganic nanoparticles, such as superior biocompatibility, prolonged circulation time, immunogenicity, homologous tumor targeting, and flexible engineering approaches on the surface, resulting in the enhanced therapeutic efficacy of inorganic nanoparticles against cancer. Therefore, a greater push toward developing biomimetic‐based nanotechnology could increase the specificity and potency of inorganic nanoparticles for effective cancer treatment. In this review, we summarize the recent advances in biological membrane‐coated inorganic nanoparticles in cancer precise therapy and highlight the different types of engineered approaches, applications, mechanisms, and future perspectives. The surface engineering of biological membrane can greatly enhance their targeting, intelligence, and functionality, thereby realizing stronger tumor therapy effects. Further advances in materials science, biomedicine, and oncology can facilitate the clinical translation of biological membrane‐coated inorganic nanoparticles.
Calcium–Zinc Phosphate Chemical Conversion Coating Facilitates the Osteointegration of Biodegradable Zinc Alloy Implants by Orchestrating Macrophage Phenotype
Authors: Da‐Wang Zhao, Chun‐Miao Du, Kang‐Qing Zuo, Yi‐Xiang Zhao, Xiao‐Qian Xu, Yi‐Bo Li, Shuai Tian, Hong‐Ru Yang, Yu‐Peng Lu, Lei Cheng, Gui‐Yong Xiao
Journal: Advanced Healthcare Materials (2022)

Zinc (Zn) alloys provide a new generation for orthopedic applications due to their essential physiological effects and promising degradation properties. However, excessive release of Zn ions (Zn2+ ) during degradation and the severe inflammatory microenvironment are not conducive to osseointegration, which is determined by the characteristics of the implant surface. Therefore, it is essential to modulate the release rate of Zn alloys by surface modification technology and endow them with anti-inflammatory and osteogenic effects. In this study, two kinds of phosphate chemical conversion (PCC) coatings with different compositions and morphological structures are prepared, namely Zn-P (with disk-like crystals) and Ca-Zn-P (with lamellar crystals). Although all the PCC-coated Zn implants have low cytotoxicity, Ca-Zn-P show better osteoimmunomodulation effects in several aspects: the induction of the M2-phenotype macrophage polarization and thus promotion of osteogenesis in vitro; the regulation of the bone immune microenvironment which is conducive to tissue regeneration and osseointegration in vivo; and the release of ions (through PI3K/AKT and Wnt signaling pathways) and the morphological structures (through RhoGTPase signaling pathways) act as possible mechanisms of M2 polarization. The Ca-Zn-P coating can be considered to provide new insights into bone immunomodulation and osseointegration.